PROJECT SUMMARY Long-term controlled release of drugs has been a problem tackled by medical practitioners, scientists and engineers alike for the past two or three decades. Despite significant efforts in the field, and the introduction of several inventions to the pharmaceutical market, the field suffers from the lack of a technique that involves easy delivery to the gastrointestinal tract (either oral or rectal route), while promising delivery of a drug over several days to weeks. A long lasting delivery mechanism has eluded scientists and engineers over years and is still a topic of active research. Here we propose to continue the development of an innovative method, in which mechanical gripping to the mucosal tissue is used to improve residence time in the GI tract. The mechanical module is tied to a cargo carrying a drug and the formulation can be administered orally or rectally without any expert help. The method will be extremely favorable to improve adherence and compliance to medicine regimens, thus significantly reducing avoidable and unwanted hospitalization. The gripping mechanism that we plan to utilize to improve retention to the gastrointestinal tract, is based on wireless actuation of self-folding robots, that can be engineered to function on administration to the gastrointestinal tract, in an autonomous fashion. We are the forerunners in the field of actuation of miniaturized robots, without any external power source, and have demonstrated the usefulness of these robotic submillimeter scale structures to carry out biopsy in the biliary tree of live pigs. Here we build on our previous results and introduce a drug carrying cargo on the grippers, such that they can be left inside the GI tract for a prolonged duration of one to several days, to maintain the required concentration of the drug for therapy. Along with the development of systemic delivery modules, the proposal also includes the development of techniques to engineer the adhesion of the gripping modules to soft friable tissues, thus promoting the local therapy of cancer. Our highly interdisciplinary team which involves gastroenterologists, engineers and pharmacologists, seek to test these hypotheses in a pig model, that has a similar GI model as humans. In particular we will deliver therapeutic dosage of an analgesic rectally, to achieve release of the drug in the blood plasma of the animal, over several days. The theragrippers and similar devices that can potentially latch onto the mucosal lining, will also be tested on an ulcerative colitis model in pigs to ensure the release of anti-inflammatory drugs like mesalamine.